Porphyrins and related pyrrolic macrocycles, particularly tetrapyrrolic macrocycles, as well as many other light absorbing compounds are currently receiving a great deal of attention with regard to photosensitized medicine, especially in the field of Photodynamic therapy (PDT)1. The therapy necessarily involves the localization of a photosensitizing agent at or near a site of disease. The sensitizer, upon illumination in the presence of oxygen, produces cytotoxic species of oxygen such as singlet oxygen or oxygen radicals, which destroy the diseased cells. As the sensitizer is innocuous at the therapeutic dose, and only becomes active on illumination with light of a specific wavelength, PDT offers the possibility of a level of control or selectivity in the treatment of diseases not found with other current methods (e.g. conventional chemotherapy). Photodynamic therapy has wide application to modern medicine, targeting diseases such as cancers, cardiovascular restenosis and plaques, psoriasis, viral infections, benign prostate hyperplasia and diabetic retinopathy. In addition, photodynamic therapy may also be useful for the sterilization of blood, an area of increasing concern, especially now with the advent of AIDS and the transmission of HIV through blood transfusions.
Most research on PDT has centered on a complex mixture consisting of ill-defined porphyrin dimers, trimers and oligomers2, which is marketed under the designation Photofrin II(copyright). This complex mixture has recently been recommended for approval in the treatment of obstructed endobronchial tumors by the Food and Drug Administration Advisory Panel. Although the mixture has demonstrated the potential benefits of PDT, it has by virtue of its composition a number of associated disadvantages. For example, each of its components has varied subcellular localizations, depending on structure and inherent differences in photophysical properties. This makes the interpretation of pharmacokinetic data difficult. In addition, the composition of the oligomers is often difficult to reproduce and changes, depending on the conditions under which a solution3 thereof is stored. Hence, the true xe2x80x9cactive componentsxe2x80x9d may vary considerably. The mixture has a less than optimal light absorption profile (630 nm, xcex5xcx9c3,000 cmxe2x88x921Mxe2x88x921). Numerous studies on light penetration through tissues show that longer wavelength light penetrates deeper into tissues4. While not all applications of PDT require deep penetration of light, many applications of PDT require the maximum depth of light penetration possible (for example the treatment of brain tumors). The mixture has a severe adverse normal skin response to light, which often lasts for up to 12 weeks5 after therapy. During this time patients must avoid strong light, as otherwise severe burns and edema occur.
Several well characterized second Generation sensitizers (SnET26, ZnPc7, BPDMA8, THPC9) are currently in phase I/II clinical trials and the continued development of new sensitizers that show improved therapeutic efficacy is crucial to the future progress of the therapy. The development of new photosensitizers that possess all the basic requirements to be effective PDT drugs is not an easy task. While the optimal photophysical properties of a second generation drug are well defined, the factors which aid in the localization of photosensitizers to tissues are not. Several investigators have attempted to ascertain structure-activity relationships in ring systems that lend themselves to chemical modification without dramatically influencing the photophysical properties of the compounds. Woodburn and coworkers, working on hematoporphyrin based analogues, have proposed that anionic compounds tend to localize in lysosomes, while cationic photosensitizers tend to localize in the mitochondria. Pandey and coworkers have suggested that the lipophilicity of the compound is important, and have demonstrated in a chlorophyll derived series that PDT effects vary with the length of the ether carbon chain. Unfortunately, many of the correlation""s found in one group of photosensitizing compounds do not transfer to different groups of photosensitizing compounds. Thus, while structure-activity relationships are valuable for a particular class of compound whose geometry and spatial arrangements vary only slightly, a different class of compound, that inherently has its own spatial and geometric parameters, must have its own structure-activity relationships investigated. This in itself is a large time consuming process with ultimately no guarantees of enhanced localization or improved PDT efficacy for the modified compound.
The instant invention is based upon the discovery of a single simple chemical modification of compounds having a pyrrolic core involving the coordination of a non-radioactive indium salt into the central cavity of the pyrrolic core to produce an indium pyrrolic complex, which markedly enhances the biological efficacy of compounds as photosensitizers for PDT.
Two isotopes of indium occur naturally: In113 and In115; the former (natural abundance 4.23%) has no radioactivity, while the latter (natural abundance 95.77%) has a half life of 6xc3x971014 years, and, as a result, is also considered to be non-radioactive. Other indium nuclides have half lives ranging from 50.0 days (for In114m) to 0.2 second (for In109m2).
Tetrapyrroles containing Indium111 (half life 2.81 days) and other metals are known in the art, being disclosed, by way of example, in Japanese Kokai 3-261786, 1991, Mauclaire et al., U.S. Pat. No. 5,268,371 and in Maier et al., U.S. Pat. No. 5,674,467, which also disclose their use for diagnostic imaging. The metal-tetrapyrrole compounds are all water soluble, and contain functional groups capable of coupling a biologically active molecule, such as an antibody, to the tetrapyrrolic nucleus. The compounds usually are prepared by reacting a porphyrin derivative with a solution of a salt of the metal to be complexed at a temperature and for a time sufficient to obtain the metal tetrpyrrole compound. For example, when a metal salt of indium111 is heated for three hours at 110xc2x0 C. in a porphyrin solution to which a mixture of acetic acid and sodium acetate has been added, an In111porphyrin is produced. Although the preparation of such metalloporphyrins is known and the compounds have been discussed in the context of radiocontrasting agents, surprisingly, so far as is known, there has been no report on the efficacy of indiumporphyrins as therapeutic photosensitizers. In view of the substantial prior art involving indium tetrapyrroles, it is indeed surprising to discover that complexes of non-radioactive indium with tetrapyrroles exhibit a marked improvement in their cytocidal effect in vivo when compared with other metallotetrapyrrole complexes.
Sakata, U.S. Pat. No. 4,849,207, discloses compounds having the following structure: 
where:
R1, R2, R4 and R6 are methyl, R8, R10, R11 and R12 are H, and R7 and R9 are CH2CH2COR13 (where R13 is a residue which results when H is removed from an amino acid), R3 and R5 are ethyl, and In is not radioactive, i.e., is In113 or In115.
Japanese Kokai 5-97857 discloses compounds having the following structure 
Where R1 is CH(OR)Me, R is alkyl, R2 is a residue derived by removing H from an amino acid, and M is 2H, Ga, Zn, Pd, In or Sn.
The Following References Are Cited Above
1. For an overview of photodynamic therapy see xe2x80x9cPhotodynamic Therapy of Neoplastic Diseasexe2x80x9d, Vol. I and II, Ed. Kessel, D., CRC Press, 1990.
2. xe2x80x9cPhotodynamic Therapy of Neoplastic Diseasexe2x80x9d, Vol. I and II, Ed. Kessel, D., CRC Press, 1990p1-12.
3. Byrne, C. J., Ward, A. D., Marshallsay, C. J. Photochem. Photobiol., 46, 575, 1987.
4. a)Svaasand, L. O., Ellingsen, R. Photochem. Photobiol. 41, 73, 1985:b) Bolin, F. P., Preuss. L. E., Cain, B. W., in xe2x80x9cPorphyrin Localization and Treatment of Tumoursxe2x80x9d. Eds. Doiron, D. R., Gomer., C. J. Alan Liss, New York, 211, 1984.
5. Razum, N., Balchum, O. J., Profio, A. E., Carstens, C. Photochem Photobiol 46, 925, 1987.
6. Kessel, D., Morgan, A. R., Garbo, G. M., Photochem. Photobiol., 54(2), 193, 1991.
7. Ginevra, F., Biffanti, S., Pagnan, A., Biolo, R., Reddi, E., Jori, G., Cancer Letters, 49, 59, 1990.
8. Aveline, B., Hasan, T., Redmond, R. W., Photochem. Photobiol., 59(3), 328, 1994.
9. Bonnett, R., White, R. D., Winfield, U., Berenbaum, M. C., Biochem. J., 261, 277, 1989.
It is an object of the present invention to provide pyrrolic compounds that absorb light at long wavelengths for use in photodynamic therapy and diagnosis of disease states.
It is another object to provide a reaction product of (A) P where P is a pyrrolic derivative and (B) In113X3 and/or In115X3 (where X is a charge balancing ion, either organic or inorganic) such as to provide the reaction product (C) PIn113nXn and/or PIn115nXn, where indium is coordinated to the pyrrolic derivative and n=1, 2, 3.
It is yet another object of the invention to provide a reaction product of (C) PIn113nXn and/or PIn115nXn with a neucleophile Y, such that a reaction product (D) PIn113nYnXz and/or PIn115nYnXz is obtained (where Y is a charge balancing ion, either organic or inorganic n=1,2,3 and z=0, 1, 2, 3).
It is still another object to provide compounds PIn113X and/or PIn115X that may be used to treat diseases such as atherosclerosis, restenosis, cancer, cancer pre-cursors, non-cancerous hyperproliferating diseases, psoriasis, macular degeneration, glaucoma and viruses, benign prostate hyperplasia, rheumatoid arthritis and to aid in the diagnosis of these disease states.